Tumor-associated inflammation and immune responses are key components in the tumor microenvironment (TME) that regulates tumor growth and progression. Tumor-associated myeloid cells (TAMCs) are a group of cells that play not only key roles in inducing tumor-associated inflammation/angiogenesis, but also regulate tumor-specific T cell responses. Thus, identification and characterization of key pathways that can regulate TAMCs are of critical importance for developing cancer immunotherapy. Our recent studies suggest that CD200-CD200 receptor (CD200R) interaction may be important in regulating the TME via affecting TAMCs. We have recently observed that expression of CD200 in melanoma cells significantly inhibits tumor formation and lung metastasis in immune-competent mice. Conversely, mice deficient for CD200R exhibits accelerated growth of CD200-positive tumors. Treatment of mice using an agonistic antibody to CD200R significantly inhibits tumor foci formation in the lungs, suggesting that enhancing CD200R signaling may inhibit tumor growth. The overall goal of this proposal is to elucidate the roles of CD200R signaling in modulating tumor associated inflammation and immunity, and its subsequent contribution to tumor growth and progression. We will also determine if targeting CD200R results in the immune intervention of tumor growth. To achieve these goals, we will first evaluate the development and progression of various CD200-positive tumors in two strains of CD200R-deficient mice. Additionally, we will generate Braf/Pten mice with or without CD200R to evaluate spontaneous melanoma formation, tumor growth, and metastasis (Aim 1). Then, we will evaluate the impacts of CD200R signaling in the induction of tumor-specific T cell responses in the TME of CD200-positive tumors (Aim 2). The establishment of these two steps will pave the way to investigate if targeting CD200R can modulate the TME and if this approach is feasible for cancer immunotherapy (Aim 3). The information generated from these studies will not only help advance our understanding of tumor pathogenesis and immunity, but also provide the rationale for CD200R-targeted immunotherapy of human cancer.